Christopher Assaid

Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial

BACKGROUND Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. METHODS In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. FINDINGS 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0.0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0.0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0.0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0.0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0.0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. INTERPRETATION Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. FUNDING Merck Research Laboratories.

A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.

Inflammatory mechanisms have been implicated in Alzheimers disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10–15%. MCI patients ⩾65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10–15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24–26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Randomized, controlled trial of telcagepant for the acute treatment of migraine

Background: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist. Methods: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2–24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports. Results: Telcagepant 300 mg was more effective (p ≤ 0.001) than placebo on all primary endpoints and the key secondary endpoint, as was telcagepant 150 mg (p ≤ 0.05). Telcagepant 300 mg showed a slight numeric advantage over telcagepant 150 mg on most measures. Telcagepant 50 mg values were numerically intermediate between placebo and telcagepant 150 mg and 300 mg. The percentages of patients with adverse experiences were 32.2% for telcagepant 50 mg, 32.0% for telcagepant 150 mg, 36.2% for telcagepant 300 mg, and 32.2% for placebo. Conclusions: This study confirmed previous findings that telcagepant 300 mg was effective at relieving pain and other migraine symptoms at 2 hours and providing sustained pain freedom up to 24 hours. In this study, telcagepant 150 mg was also effective. Telcagepant was generally well tolerated.

Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine

Aim The aim of this trial was to evaluate the efficacy and tolerability of ubrogepant (MK-1602), a calcitonin gene-related peptide receptor antagonist (CGRP-RA), for the acute treatment of migraine. Methods This double-blind, placebo-controlled study randomized 834 participants to treat one migraine attack with ubrogepant 1 mg, 10 mg, 25 mg, 50 mg, 100 mg, or placebo in a 1:1 ratio. The co-primary endpoints were pain freedom and headache response at two hours. The first primary hypothesis tested the dose-response trend for two-hour pain freedom using a logistic regression model. Subsequent hypotheses tested the effects of each dose on the co-primary endpoints, using a closed sequential testing procedure to control for multiplicity. Results A total of 527 participants received ubrogepant and 113 received placebo. A positive response trend in the proportion of participants achieving two-hour pain freedom was demonstrated (p < 0.001). Ubrogepant 100 mg was significantly superior to placebo for two-hour pain freedom (25.5% vs 8.9%) but not for two-hour headache response. Per the prespecified multiplicity strategy, this nonsignificant result precluded further formal hypothesis testing, although the 50 mg and 25 mg doses demonstrated nominal significance over placebo for two-hour pain freedom (unadjusted p < 0.05). Overall, adverse events were similar between ubrogepant and placebo. Conclusion This trial supports ubrogepant’s efficacy and provides further evidence that CGRP-RAs are viable options for the acute treatment of migraine.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: Results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design

Background Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. Methods Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6–17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for <40 kg, 10 mg for ≥40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12–17-year-olds. Results A higher proportion of 12–17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12–17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6–17-year-olds. Conclusion Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12–17 and 6–17 years. Trial Registration ClinicalTrials.gov NCT01001234

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

Aim The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. Methods We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (−2 days to +3 days of menses onset) and ≥5 moderate or severe migraines per month prior to entering the trial. Results Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥3× normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference −0.5 day (95% CI: −1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference −0.4 day (95% CI: –0.5, –0.2), nominal p < 0.001). Conclusions Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimers disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Sustained pain freedom and no adverse events as an endpoint in clinical trials of acute migraine treatments: Application to patient-level data from a trial of the CGRP receptor antagonist, telcagepant, and zolmitriptan*

Background: Endpoints used to evaluate the efficacy of acute anti-migraine drugs do not measure the tolerability. Sustained pain-free response with no adverse events has been recommended as a composite endpoint which measures the efficacy and tolerability attributes that patients desire. Methods: The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, and zolmitriptan in the acute treatment of migraine. Endpoints were 2–24-hour sustained pain freedom and no adverse events from 0–24 hours (SPF24NAE), 2–24 hour sustained pain relief and no adverse events from 0–24 hours (SPR24NAE), pain freedom at 2 hours and no adverse events from 0–24 hours (PF2NAE), and pain relief at 2 hours and no adverse events from 0–24 hours (PR2NAE). Results: Compared with placebo, both telcagepant 300 mg and 150 mg achieved nominal superiority (p values <.05) for SPF24NAE, SPR24NAE, PF2NAE and PR2NAE. Zolmitriptan 5 mg showed nominal superiority versus placebo for SPF24NAE, SPR24NAE and PF2NAE, but not PR2NAE. Telcagepant 300 mg showed nominal superiority versus zolmitriptan for SPF24NAE, SPR24NA and PR2NAE. Conclusion: Composite efficacy-plus-tolerability endpoints may be useful for facilitating comparisons between treatments.

Long-Term Open-Label Safety Study of Rizatriptan Acute Treatment in Pediatric Migraineurs

To evaluate the safety/tolerability of rizatriptan in the long‐term acute treatment of migraine in pediatric patients.